Characterizing Lung Inflammation in Agricultural Respiratory Exposures Between the Sexes

Agriculture workers, in Saskatchewan and worldwide, are exposed to numerous potential pollutants, including grain dust and pesticides. Although female workers make up approximately 25% of the agricultural working population, the majority of current research on the respiratory and inflammatory effects in agriculture has been conducted on male animal models and workers; very little has been studied of the female response. Females are able to mount a more robust and efficient early immune response leading to improved prognosis in surviving acute infections arising from a variety of pathogens (bacteria, viruses, trauma) compared to males. However, increased efficiency mean females are more predisposed to developing autoimmune diseases. Agriculture workers are commonly exposed to more than one pollutant at a time; how the interaction between glyphosate and lipopolysaccharide (a component of grain dust) will differentially affect the sexes is not known. Currently, there has been minimal work done to evaluate how a respiratory glyphosate exposure may differentially impact the sexes. The following study evaluates the differences in the inflammatory respiratory response between the sexes following a short-term agriculture respiratory exposure and is the first study to do so. It uses a mouse model. C57BL/6 mice were intranasally treated with glyphosate (1µg), lipopolysaccharide (LPS) (0.5µg), combined LPS + glyphosate (LPS: 0.5 µg + glyphosate: 1µg), or Hank’s Balanced Salt solution (HBSS) for 5 days. These studies were performed to characterize the inflammatory effects in mice following a short-term intranasal exposure to LPS plus glyphosate including 1) evaluating inflammatory effects of the combined exposure to glyphosate and LPS in female mice compared to exposure to each individual agent; 2) comparing the female response to the combined LPS plus glyphosate exposure vs. the male response; and 3) observing the structural lung changes of the combined exposure to glyphosate and LPS in female mice as measured using multiple image radiography. Female mice, exposed to LPS and glyphosate for 5 days showed higher levels of inflammatory mediators compared to control animals, or those treated with only LPS or glyphosate. Inflammatory mediators, such as proinflammatory cytokines, were elevated in the LPS plus glyphosate treated animals, indicating that after 5 days, the addition of the glyphosate impacts the ability of female mice to ameliorate the effects of LPS, compared to the animals treated only with LPS or glyphosate. Further, this study revealed that female mice display a different inflammatory respiratory response compared to male mice. Female mice demonstrated: less lung architecture damage across treatment groups; significantly lower levels of inflammatory markers; and lower levels of proinflammatory cytokine expression as compared to male mice. This is the first study to validate that a significant difference exists between the male and female immune response following a short-term agriculture respiratory exposure to LPS and glyphosate. Finally, comparisons of lung effects using multiple techniques (multiple image radiography, and histology) were utilized to evaluate a short-term common agriculture respiratory exposure in female mice. Histology revealed greater recruitment of cells into alveolar regions in the lungs of the mice and disruption to the bronchial epithelium from the combined LPS and glyphosate treated group as compared to other treatment groups. MIR images revealed mice exposed to LPS and both LPS plus glyphosate showed compromised lung tissue compared to other treatment groups. Taken together, these results reveal that female mice exposed to the combination of LPS and glyphosate displayed physiological and structural effects that were different from mice exposed to LPS or glyphosate alone. However, the inflammatory effects of the combined exposure were not as pronounced in the female mice compared to the male mice, highlighting the importance of using a structural evaluation technique such as multiple image radiography to reveal the impact to the lungs of such exposures. Overall, we observed that female mice, exposed to an agriculturally relevant concentration combining LPS plus glyphosate for 5 days, exhibited respiratory inflammatory effects significantly different compared to each single exposure. Additionally, we demonstrated that there is a significantly different respiratory inflammatory response between the females and males at 5 days of LPS plus glyphosate exposure. While the precise mechanisms remain to be elucidated, the differences may be due to the protective effects of estrogen. This study is the first research to characterize a short term respiratory inflammatory exposure to LPS plus glyphosate in female mice, to compare these results to those obtained from male mice, and to utilize multiple image radiography technology to do so. We were able to detect the differences between exposure groups using MIR and refined this technique during our study. The results suggest that MIR may become a paramount tool in future lung imaging experiments.

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